title: Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake.
abstract: Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion-resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization-active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion-resistant alcohol intake.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Taban
authors.initials: T
authors.lastname: Seif
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Chang
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Simms
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Gibb
authors.forename: Jahan
authors.initials: J
authors.lastname: Dadgar
authors.forename: Billy T
authors.initials: BT
authors.lastname: Chen
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.forename: F Woodward
authors.initials: FW
authors.lastname: Hopf
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D000679:Amygdala / Q000737:chemistry; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D001426:Bacterial Proteins / Q000032:analysis; D002540:Cerebral Cortex / Q000737:chemistry / Q000503:physiopathology*; D003216:Conditioning, Operant; D004351:Drug Resistance / Q000502:physiology*; D000431:Ethanol / Q000097:blood; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D025602:Halorhodopsins / Q000032:analysis; D008164:Luminescent Proteins / Q000032:analysis; D008297:Male; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009714:Nucleus Accumbens / Q000503:physiopathology*; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000737:chemistry / Q000503:physiopathology*; D011803:Quinine / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000427:Alcohol Deterrents; D001426:Bacterial Proteins; D018691:Excitatory Amino Acid Antagonists; C549071:Grin2d protein, mouse; D025602:Halorhodopsins; D008164:Luminescent Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D010880:Piperidines; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; C054562:yellow fluorescent protein, Bacteria; D000431:Ethanol; C056639:2-amino-5-phosphopentanoic acid; D011803:Quinine; D014633:Valine; C010739:ifenprodil